Farnesoid x receptor modulators

Abstract

The present invention provides a compound of formula (I):or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1, R2, R3, R4, R5, and R6 are as described herein. The present invention relates generally to selective FXR agonists and to methods of making and using them.

1 . A method of treating fibrosis or one or more symptoms of intrahepatic cholestasis or extrahepatic cholestasis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:
 R 1  is hydroxyl; 
 R 2  is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R a ; 
 R 3  is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R b ; 
 R 4  is alkyl, alkenyl, alkynyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R c ; 
 R a , R b , and R c  are each independently halogen or hydroxyl; 
 R 5  is hydroxyl, OSO 3 H, OSO 3   − , OCOCH 3 , OPO 3 H 2 , OPO 3   2− , or hydrogen; and 
 R 6  is hydroxyl, OSO 3 H, OSO 3   − , OCOCH 3 , OPO 3 H 2 , OPO 3   2− , or hydrogen; 
 
       or taken together R 5  and R 6  with the carbon atom to which they are attached form a carbonyl. 
     
     
         2 . The method of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. 
     
     
         3 . The method of  claim 1 , wherein one of R 2  or R 3  is hydroxyl and the remaining R 2  or R 3  is hydrogen. 
     
     
         4 . The method of  claim 1 , wherein one of R 5  or R 6  is hydroxyl and the remaining R 5  or R 6  is hydrogen. 
     
     
         5 . The method of  claim 1 , wherein R 2  is hydroxyl and R 3  is hydrogen. 
     
     
         6 . The method of  claim 1 , wherein R 5  is hydroxyl and R 6  is hydrogen. 
     
     
         7 . The method of  claim 1 , wherein R 2  and R 5  are each hydroxyl and R 3  and R 6  are each hydrogen. 
     
     
         8 . The method of  claim 1 , wherein R 4  is alkyl. 
     
     
         9 . The method of  claim 1 , wherein R 4  is unsubstituted alkyl. 
     
     
         10 . The method of  claim 1 , wherein R 4  is ethyl. 
     
     
         11 . The method of  claim 1 , having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof. 
     
     
         12 . The method of  claim 1 , for treating fibrosis. 
     
     
         13 . The method of  claim 1 , for treating one or more symptoms of intrahepatic cholestasis or extrahepatic cholestasis. 
     
     
         14 . The method of  claim 12 , wherein the fibrosis is fibrosis due to pathological conditions or diseases, fibrosis due to physical trauma, fibrosis due to radiation damage, fibrosis due to exposure to chemotherapeutics, liver fibrosis, fibrosis of the kidneys, fibrosis of the lung, or fibrosis of the intestine. 
     
     
         15 . The method of  claim 12 , wherein the fibrosis is due to a disease selected from primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver, obesity, non-alcoholic steatohepatitis, cystic fibrosis, hemochromatosis, auto-immune hepatitis, and steatohepatitis. 
     
     
         16 . The method of  claim 12 , wherein the fibrosis is fibrosis secondary to surgical scarring, accidental physical trauma, burns, or hypertrophic scarring. 
     
     
         17 . The method of  claim 13 , wherein the one or more symptoms of intrahepatic cholestasis or extrahepatic cholestasis is biliary atresia, obstetric cholestasis, neonatal cholestasis, drug induced cholestasis, or cholestasis arising from Hepatitis C infection.